Requirement for self-recognition by T-helper cells of macrophage and B cell Ia determinants has been analyzed in vitro and in vivo. The self-recognition repertoires of T cells from A-- greater than Axb, AxB-- greater than A, and A-- greater than B radiation bone marrow chimeras were restricted to the recognition of host, not donor, MHC determinants. While activation of T-helper cells invariably required self-recognition of macrophage Ia determinants, T-helper cell activation of B cells did not necessarily require T cell recognition of B cell Ia determinants. Indeed, it was found that those B cell responses which require T cell recognition of B cell Ia determinants were mediated by the Lyb5-B cell subpopulation, whereas B cell responses which were not T-B restricted involved the Lyb5+ B cell subpopulation.